1, 4alpha-dimethyl-1-aroyl-7-isopropyl-1, 2, 3, 4, 9, 10, 1alpha, 4alpha-octahydrophenanthrene derivatives



United States Patent 1,4a Dl1VIETHYL-1-AROYL-7 ISOPROPYL- 1,2,3,4,9,10,1a,4a OCTAHYDROPHENAN- THRENE DERIVATIVES Robert P. Jacobsen, Shrewsbury, Mass., assignor to G. D. Searle & Co., Chicago, 111., a corporation of Illinois No Drawing. Application July 23, 1952, Serial No. 300,487

8 Claims. (Cl. 260-99) The present invention relates to a new group of phenanthrene derivatives. The 1,4a-dimethyl-1-aroyl-7- isopropyl 1,2,3,4,9,10,1a,4a octahydrophenanthrene derivatives which constitute this invention are represented by the following structural formula CH: (JO-Ar AK HzC2 C? %=O In the foregoing structural formula R is a member of the class consisting of H, ---OH, -O-(1ower alkyl) and OCO-(lower alkyl) radicals. Examples of the lower alkyl groups in these alkoxy and acyloxy radicals are methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, sec.- butyl, tert.-butyl, amyl, hexyl and the like. The radical Ar is a monocyclic aroyl hydrocarbon radical which can be a phenyl or a lower alkylated phenyl radical such as tolyl or xylyl.

This invention furnishes valuable compounds having the activity of female sex hormones. By acetylene addition, by reduction with lithium aluminum hydride and by Reformatzky condensation valuable new synthetic products with hormonal action are made available.

In the preparation of the compounds claimed in this application I prefer to use as the starting material the ketones of the structural formula 0 CH: i l-Ar These are prepared from the corresponding abietyl halides by reaction with the arylcadmium compounds. In the case of the 6-hydroxy derivatives it is necessary to protect this radical by etherification or esterification. The ketones of the above formula are then oxidized with chromic acid, suitably in strong acetic acid solution.

My invention will appear more fully from the following examples. It should be understood, however, that these examples are given by way of illustration only and that the invention is not to be construed as limited in spirit or in scope by the details set forth. It will be apparent to those skilled in the art that many modifications in materials and methods can be made without departing from the scope of the invention. In each of these examples temperatures are given uncorrected in degrees centigrade C.), pressures during vacuum distillation in millimeters (mm.) of mercury and quantities in grams (g.) and milliliters (ml.).

2,704,283 Patented Mar. 15, 1955 ice Example 1 Crude dehydroabietyl chloride is prepared by dissolving 150 g. of dehydroabietic acid (dried at C., melting at 172-l72.5 C.) in ml. of thionyl chloride and heating the solution for 2 hours at 30-35 C. under nitrogen. Following distillation of the excess thionyl chloride under diminished pressure, the viscous residue is diluted with 200 ml. of toluene and the distillation repeated. A solution of the residue in 450 ml. of ether and 300 ml. of toluene is then added with stirring to an excess of diphenyl cadmium reagent prepared from 14.6 g. of magnesium turnings, 62.8 ml. of bromobenzene and 60.5 g. of cadmium chloride in a mixture of 300 ml. of ether and 300 ml. of toluene. The mixture is heated gently at reflux temperature for 45 minutes and then cooled with ice and acidified with hydrochloric acid. The ether-toluene layer is washed successively with dilute hydrochloric acid, water, dilute sodium hydroxide, water and saturated sodium chloride solution; the alkaline wash serves to remove a small amount of acidic material which is discarded. The solution is distilled to remove most of the ether and then further concentrated 0 dry; it thoroughly. The product has the structural ormu a The dehydroabietophenone thus obtained is used directly in the subsequent reactions. A sample, in concentrated toluene solution, was subjected to steam distillation and yielded a non-volatile resin readily soluble in pentane. On vacuum distillation at about l85190 C. and 0.1 mm. pressure followed by chromatography on alumina, substantially pure dehydroabietophenone was obtained as a nearly colorless stitf resin.

Example 2 A solution of 6.2 g. of the undistilled resin of dehydroabietophenone and 6 g. of aluminum isopropoxide in 150 ml. of absolute isopropanol is boiled for about 20 hours with slow distillation of the solvent through a ,packed jacketed column maintained at 77-78 C. The isopropanol is distilled more rapidly toward the end of the reaction until the residual volume is reduced to about 50 ml. The residue is treated with cold dilute hydrochloric acid and extracted with ether. The ether layer after washing with water and saturated sodium chloride is dried and distilled, afiording a nearly colorless syrup which crystallizes partly on rubbing with pentane forming small needles. Upon repeated recrystallization from ether-pentane or heptane, needles of the u-phenyldehydroabietinol are obtained which melt at about -161 C. The product has the structural formula H3O CH(OH) CoHls CH(CH:):

Example 3 For the preparation of larger quantities of a-phenyldehydroabietinol the following method is convenient. 200 ml. of a concentrated toluene solution of dehydroabietophenone (about 0.5 g./ml.) are mixed with a clear decantate prepared from 15 g. of aluminum turnings, a

trace of mercuric chloride and 2500 ml. of isopropanol. After slow distillation of this solution for 30 to 40 hours the residue (700-900 ml.) is diluted with stirring with about 500 ml. of water, cooled internally and externally with ice, and rendered slightly acid with Congo red, and with concentrated hydrochloric acid. This acidity is maintained While the stirred mixture is gradually diluted with 1200 ml. of water causing precipitation of about 79 g. of crude a-phenyldehydroabietinol.

Example 4 The benzoate of the a-phenyldehydroabietinol is prepared by heating for 2 hours on the steam bath of 2 g. of the phenylcarbinol with ml. of benzoyl chloride in 20 ml. of pyridine. On recrystallization from a mixture of acetone and methanol the product forms rosettes of small leaves melting at about 151.5-152.5 C. after drymg at 80 C. The product has the structural formula OOC-CaHs Hac CH(CHa)2 The acetate of a-phenyldehydroabietinol, similarly prepared with acetic anhydride in pyridine, crystallizes from methanol 1n clumps of short needles melting at about IDS-109 C. after drying at 80 C.

Example 5 0.78 g. of the noncrystalline fractions accompanying crphenyldehydroabietinol in the preparation according to the methods of Examples 2 and 3 are heated in a sealed tube with 1.5 g. of 2,5-dinitrobenzoyl chloride in ml. of pyndme for 5 hours at 95 C. After treatment with water the reaction mixture is extracted with ether and the solvent layer washed successively with dilute hydrochlorlc acid, water, dilute sodium carbonate, water, and saturated sodium chloride. The orange oil remaining after dist llation of the dried ether solution is moistened with a mixture of acetone and methanol causing crystallization of a pale yellow solid melting at 199-205 C. Upon recrystallization from a mixture of acetone and methanol and acetone alone, small medallion-shaped granules are formed which melt at 2055-207 C. 0.96 g. of the dimtrobenzoate of the isomeric u-phenyldehydroabietinol thus obtained are saponified with 0.5 g. of sodium hydroxide in ml. of methanol and 20 ml. of benzene. After concentration of the hydrolysis mixture under diminished pressure, the residue is taken up in ether and the solution is washed with Water and saturated sodium chloride. The residue from the dried ether-benzene solutron is then dissolved in methanol and poured with stirring into a dilute solution of sodium chloride. The white precipitate thus formed is collected, washed and air dried. The product can be sublimated at about 90-135 C. bath temperature and 0.001 mm. pressure. The sublimate which is obtained in the form of a brittle milky glass, smters at 45 C. and becomes mobile enough to flow at 70 C. The product has the same structural formula as that of Example 2 but is the epirner, which has the opposite configuration at the a-hydroxylated carbon atom.

A solvated isocarbinol is encountered upon saponification of the dinitrobenzoate with aqueous methanol. The

dried precipitated isocarbinol is moistened with methanol whereupon the chalky powder slowly changes to a crystalline solid. This is recrystallized from methanol forming laths sintering at 5256 C. The melting point is apparently a phase change from solvated crystals to viscous solution for, on continued heating, fine bubbles form in the melt obscuring the disappearance of the last solid particles.

Example 6 0.17 g. of the sublimed a-phenylisodehydroabietinol are heated with 0.4 g. of 3,5-dinitrobenzoyl chloride in 4 ml. of pyridine in a sealed tube at 95 C. for 5 hours. 'he resulting dinitrobenzoate melts at about 201.5-204" 4 Example 7 11 C GH(OH) CaHs CH(CH:):

Example 8 With 3,5-dinitrobenzoyl chloride, a-phenyl-9-oxodehydroabietinol forms the dinitrobenzoate which separates from methanol in very fine needles which melt at about 185-202 C. with considerable sintering.

A dinitrophenylhydrazone is obtained by heating 1 g. of a-phenyl-9-oxodehydroabietinol with 0.6 g. of 2,4-dinitrophenylhydrazine in methanol containing a small amount of acetic acid in a sealed tube for 19 hours at l25-l30 C. There is obtained a mixture of orange-red needles of unreacted hydrazine and of red-brown platelets of the hydrazone. The latter, on recrystallization from a mixture of methanol and chloroform, forms very thin Vermilion needles which melt at about 259 C. with decomposition.

Example 9 2 g. of methanol solvated a-phenylisodehydroabietinol are fused at C. in a stream of dry nitrogen. The resulting anhydrous resin is heated on the steam bath for 2 hours with 5 ml. of acetic anhydride and 4 ml. of pyridine. The product is taken up in ether and the washed ether solution is dried over anhydrous sodium sulfate, filtered and evaporated. The residue is dissolved in 20 ml. of methanol and poured into 200 ml. of stirred cold water containing a small amount of sodium chloride. The resulting white precipitate is collected on a filter and washed with water.

1 g. of this acetate of u-phenylisodehydroabietinol is dissolved in 15 ml. of acetic acid and stirred at 20 C. with the addition of 2.5 ml. of a solution (0.25 g./ml.) of chromic anhydride in acetic acid. After allowing the solution to stand for 6 hours at 30 C., it is di' luted with water containing sodium sulfite and the precipitated epirner of a-phenyl-9-oxodehydroabietinyl acetate is saponified and washed.

Example 10 A solution of 0.5 g. of a-phenyl-9-oxodehydroabietinol, as obtained in Example 7, in 7 ml. of acetic acid is treated with 1 ml. of chromic acid solution as used in Example 7 and allowed to stand for 5.5 hours at 26 C. The product crystallizes from aqueous methanol in hexagonal tablets melting at about -101" C. This is dissolved in carbon tetrachloride and decolorized by percolation through an alumina column. The colorless residue after repeated crystallization from aqueous methanol melts at about 103-104 C. The 9-oxodehydroabietophenone has the structural formula HtC COCeHs Example 11 0.5 g. of the epimer of a-phenyl-9-oxodehydroabietinol, obtained in Example 9, are oxidized with 0.25 g. of chrome anhydride and 8 ml. of acetic acid at 22-24 C. for hours. The resulting 9-oxodehydroabietophenone is recrystallized from aqueous methanol. A mixed sample with the product of Example 10 and of Example 12 gives no depression.

Example 12 To a solution of 8.48 g. resinous dehydroabietophenone, distilled at 185-190 C. and 0.1 mm. pressure, in 100 ml. of acetic acid a solution of 8.75 g. of chromic anhydride in 35 ml. of 80% acetic acid is added gradually at -20 C. After standing at 35 C. for 6 hours, the mixture is poured into 500 ml. of cold half-saturated sodium sulfate solution and the excess chromic acid is reduced with sodium sulfite. The resinous product is extracted with ether and the extract washed successively with water, dilute sodium carbonate, water and saturated sodium chloride. The bright yellow oil remaining after distillation of the ether crystallizes from a mixture of carbon tetrachloride and hexane. Decolorization by percolation through an alumina column yields pure 9-oxodehydroabietophenone melting at about 103104 C.

Example 13 Crystalline methyl 6-hydroxydehydroabietate (L. F. Fieser and W. P. Campbell, I. A. C. S., 61, 2532; 1939; W. P. Campbell and M. Morgana, ibid., 63, 1841; 1941) melting at 156.5-157.5 C. is saponified with 25% methanolic potassium hydroxide and the amorphous acid, precipitated by acidification of the diluted alkaline solution with hydrochloric acid, is collected, washed and dried at 50 C. The acid is acetylated with acetic anhydride in pyridine and the washed and dried product is obtained in the form of an amorphous powder by pouring its methanol solution into stirred cold water containing a little sodium chloride. This crude acetoxy acid is converted to the fi-acetoxydehydroabietyl chloride with thionyl chloride as in Example 1. A solution of this chloride (prepared from 6.17 g. crystalline methyl G-hydroxydehydroabietate) in a mixture of ether and toluene is then added to the diphenyl cadmium reagent prepared from 1 g. of magnesium, 4.4 ml. of bromobenzene and 4 g. of cadmium chloride. After warming the reaction mixture for one hour, the product is cooled with ice and acidified with hydrochloric acid. The ether-toluene layer is washed successively with dilute hydrochloric acid, water and saturated sodium chloride solution. The solution is distilled to remove most of the ether and then steam distilled to remove toluene and diphenyl. The solid residue is saponified by refluxing for one hour with 100 ml. of methanol containing 10 ml. of 50% aqueous potassium hydroxide after which the diluted alkaline solution is poured into an excess of cold hydrochloric acid. The resulting precipitate is crystallized from aqueous methanol from which it separates in small leaves melting at about 155- 156.5 C. Repeated crystallization raises the melting point to about 160.5161.5 C. Another modification of the same 6-hydroxydehydroabietophenone can be obtained which melts at about 168.5170.5 C. The structural formula is 11:0 0 O CtHa CH(CHs)s Example 14 3.8 g. of 6-hydroxydehydroabietophenone and 6 ml. of acetic anhydride in 10 ml. of pyridine are heated on the steam bath for 2 hours. The resulting 6acetoxydehydroabietophenone, recrystallized from methanol, gcggmss glistening leaves which melt at about 162.5-

6 Example 15 0.42 g. of 6-hydroxydehydroabietophenone are suspended in 10 ml. of 25 sodium hydroxide. The suspension is stirred and maintained at 70-80 C. during the portionwise addition of 2 ml. of dimethyl sulfate. The 6-methoxydehydroabietophenone is recrystallized from methanol and melts at about 1345-1365 C.

Example 16 A cold stirred suspension of 1.05 g. of 6-acetoxydehydroabietophenone in 15 ml. of acetic acid are treated with 2.5 g. of chromic anhydride in 10 ml. of 80% acetic acid. After addition of the oxidant the mixture is allowed to stand for 3.5 hours at 30 C. and diluted with water. 1.08 g. of the crude 6-acetoxy-9-oxodehydroabietophenone is refluxed for 30 minutes with 5 ml. of 25% aqueous sodium hydroxide in 50 ml. of methanol. The hydrolysis mixture is diluted with water and acidified with dilute hydrochloric acid. The 6-hydroxy-9- oxodehydroabietophenone is crystallized from acetone or a mixture of acetone and methanol yielding needles melting at about 233.5-236.5 C. The larger needles decrepitated explosively on vacuum drying. The product has the structural formula CH(CHt)a Example 17 A solution of 1 g. of 6-hydroxy-9-oxodehydroabietophenone is heated with 1.5 ml. of acetic anhydride in 3 ml. of pyridine on the steam bath for 2 hours. The acetate is crystallized from aqueous methanol and dried at 80 C. The leaves of the 6-acetoxy-9-oxodehydroabietophenone melt at about 1l4115.5 C.

CH3 CO.CuH5

CH(CHa)2 O (LOH:

Example 18 CH3 CO.CsH5

Example 19 A solution of 0.15 g. of 6-hydroxy-9-oxodehydroabietophenone in methanolic hydroxylamine is heated in a sealed tube at C. for 3 hours. The resulting oxime crystallizes from aqueous methanol in short rods melting at about 234-238 C. with decomposition, the melt efiervescing and becoming dark red in color.

' 7 I claim: 1. The 1,4a-dimethyl-1-aroyl-7-isopropyl-1,2,3,4,9,10,- 1a,4a-octahydro-9-phenanthrones of the structural formula CH: C-Ar CH(CH:):

0 OH: HF-At wherein Ar is a monocyclic aryl hydrocarbon radical containing less than nine carbon atoms.

3. 9-oxodehydroabietophenone.

4. The l-aroyl 6 hydroxyl-l,4a-dimethyl-7-isopropyl- 1,2,3,4,9,l0,1a,4a-octahydro-Q-phenanthrones of the structural formula wherein Ar is a monocyclic aryl hydrocarbon radical containing less than nine carbon atoms.

5. 6-hydroxy-9-oxodehydroabietophenone.

6. The process of preparing the compounds of the structural formula GE; (JO-Ar CH(CH:):

wherein R is a member of the class consisting of hydrogen, hydroxy, lower alkoxy and lower alkanoyl radicals, and Ar is a monocyclic aryl hydrocarbon radical containing less than nine carbon atoms, which comprises the oxidation with chromic acid at a temperature below 60 C. of a compound of the structural formula CH1 X-Ar wherein X is a member of the class consisting of carbonyl and carbinol radicals and Ar and R are defined as hereinabove.

7. The process of preparing the compounds of the structural formula CH: C O-Ar wherein Ar is a monocyclic aryl hydrocarbon radical containing less than nine carbon atoms, which comprises the oxidation with chromic acid at a temperature below 60 C. of a compound of the structural formula CH: O O-Ar CH(CH:)2

8. The process of preparing the compounds of the structural formula CH1 COAr wherein Ar is a monocyclic aryl hydrocarbon radical containing less than nine carbon atoms, which comprises the oxidation with chromic acid at a temperature below 60 C. of a compound of the structural formula CH: C O-Ar References Cited in the file of this patent UNITED STATES PATENTS 2,656,343 Ritchie Oct. 20, 1953 OTHER REFERENCES Zeis s: Studies on Resin Acids, Journal American Chemical Society, vol. 70, pp. 858-860 (1948). 

1. THE 1,4A-DIMTHYL-1-AROYL-7-ISOPROPYL-1,2,4,9,101A,4A-OCTAHYDRO-9-PHENANTHRONES OF THE STRUCTURAL FORMULA 